Alternatively spliced variants of the CD44 molecule have been found to be associated with invasive and metastatic potential of cancer cells and poor prognosis in several types of carcinoma. We have examined expression of CD44 in normal and cancerous tissues of the endometrium as well as in cell lines established from patients with endometrial cancers by the combination of reverse transcription-polymerase chain reaction and Southern blot hybridization and by cell surface staining with antibodies to CD44. Of eight cancer cell lines tested, two lines, HOOUA and HEC50B, both of which are possibly potential candidates for metastasis, expressed a very small amount of mRNA for CD44. Variant forms of CD44 were expressed in 9 of 11 (81.8%) normal endometria, whereas 8 of 47 (17.0%) endometrial carcinomas showed expression of the variants. Hyperplasia samples displayed the variant expression in 42.9% of specimens (the value was between those of the normal and cancerous cells) and none of 3 in Müllerian mixed tumors. There was a significant difference in frequencies of CD44 variant expression between normal and cancerous tissues. Furthermore, lymph-vascular space involvement of cancer cells was observed to be statistically significant in the CD44-negative group as opposed to the positive group. Reverse transcription-polymerase chain reaction and Southern blot hybridization clearly demonstrated that normal endometrial tissues express the standard CD44 form as well as the variant form. Immunohistochemical examination of normal endometrium revealed that intense staining was seen on the gland cells at the basement membrane side, and less intense staining was seen between the gland cells. These results suggest that CD44 could play important roles in the function of normal endometrium and that reduced CD44 expression might be related to the metastasis of endometrial cancer cells through lymph-vascular space.